Isoxazolyl-substituted benzindenediones

ABSTRACT

Processes and intermediates leading to steroids of the 19-nor and estrane series are described. The A-ring of the steroid is constructed onto a BCD-tricyclic intermediate by degradation of a 3,5-disubstituted-4-isoxazolylmethylene group to a 3-oxoalkyl group, followed by cyclization.

United States Paten Saucy et a1.

[ 51 Sept. 12, E972 ISOXAZOLYL-SUBSTITUTED BEN ZINDENEDIONES Inventors: Gabriel Saucy, Durrmattweg 23, 4144 Arlesheim, Switzerland; John William Scott, 125 Fells Road, Essex Fells, NJ. 07021 Filed: May 21, 1970 Appl. No.: 39,560

Related US. Application Data Continuation-impart of Ser. No. 778,314, Nov. 22, 1968.

US. Cl. ..260/307 H Int. Cl. .C07d 85/22 Field of Search .260/307 l-l References Cited UNITED STATES PATENTS 3,502,660 3/1970 Butler et a1. ..260/240 Primary Examiner-Alex Mazel Assistant Examiner-R. V. Rush Attorney-Samuel L. Welt, Jon S. Saxe, Bernard S, Leon, William H. Epstein and George M. Gould [57] ABSTRACT 7 Claims, No Drawings lSOXAZOLYL-SUBSTITUTED BENZINDENEDIONES CROSS-REFERENCE TO RELATED APPLICATIONS 5 This application is a continuation-in-part of our copending US. Pat. application Ser. No. 778,314, filed Nov. 22, 1968.

BACKGROUND OF THE INVENTION In recent years, much effort has been devoted to the total synthesis of steroids. The medicinally important 19-nor-steroids have been the subjectof a large number of chemical investigations, cf. C. Djerassi, Science, 151, 1055 (1966); L. Velluz et al., Tetrahedron Supplement 8, Part- II, 1 495 (1966). l9-Nor-steroids have been prepared in accordance with prior art teachings by the reduction of Ring A aromatic steroids either chemically [A. L. Wilds et al., J. Am. Chem. Soc. 75, 5366 (1953)] or photolytically [.I. A. Waters et al., J. Am. Chem. Soc. 89, 1022, (1967)]. Other methods known in the art for the preparation of l9-nor-steroids inclu'de oxidation of the C-l9 methyl group of a steroid to the corresponding carboxylic acid followed by acidic decarboxylation of the resulting l9-carboxy-A -3-keto system. [A. Bowers et al., J. Am. Chem. Soc. 84, 3204 (1962).] The present invention relates to certainpolycyclic compounds and processes for their synthesis. The novel intermediates and processes of this invention provide a new synthetic route for the preparation of pharmaceutically valuable l9-nor-steroids. Further, the intermediates and processes of the invention provide a novel route for the preparation of pharmaceutically valuable estrones. In synthesis of steroidal materials, steric considerations are of great significance. The most used steroidal compounds are those having a C/D-trans-ring junction with the substituent in the 13-position being in the ,B-configuration. The present invention provides a facile total synthesis of 13B-C/D- trans-steroidal materials. This desirable result is obtained via a unique asymmetric induction followed by subsequent stereospecific reaction steps.

SUMMARY OF THE INVENTION A 3,5-disubstituted-4 isoxazolylmethylene group is employed as a precursor of the steroidal Ring A in this synthesis. The novel use of this group as a precursor of the steroidal Ring A provides animproved method for obtaining extremely high yields of optically active pharmaceutically valuable steroid end-products. This is in part due to the chemically stable nature of the isoxazole group to the acids, bases, hydrogenations and otherprocess perameters employed throughout the synthesis. By-product formation has been substantially reduced by the processes of this invention, thereby facilitating costly separating and purifying procedures. The substantial elimination of byproduct formation also contributes to the obtention of the high endproduct yields. Further, it has been found that by means of the resolutions of starting materials and subsequent stereospecific reaction steps of the processes of this invention, the direct obtention of optically active end-products is greatly facilitated.

In one aspect, this invention relates to substitutedisoxazole starting materials of formulas Il-a and 11-h,

intermediates therefor and their method of preparation via a Wittig-type reaction of a phosphonium ylid of formula D and acrolein dimer (formula E) in accordance with Reaction Schemes A and B.

In Reaction Schemes A and B, R is selected from the group consisting of lower alkyl and hydrogen; R is selected from the group consisting of lower alkyl, lower alkylaryl, aralkyl and hydrogen; X is an inorganic anion derived from a mineral acid; R R' and R';, are independently selected from the group consisting of lower alkyl, phenyl and phenyl-lower alkyl; R is selected from the group consisting of mono-hydrocarbylamino and di-hydrocarbylamino and acid salts thereof; R is lower alkyl; R, is selected from the formulas R NH and R' O wherein R is an optically active hydrocarbyl residue.

REACTION SCHEME A wherein R R X, R R and R are defined as aforesaid.

REACTION SCHEME B.

O v m N I II-a wherein R R R R R R R and R are defined as aforesaid.

In another aspect, this invention is directed to the process and compounds represented schematically in Reaction Scheme C. Thus, the 3-substituted-6aB-alkyb cyclopentaLf][l]-benzopyrans or naptho[2,l-b]pyrans of formula l-a are prepared by reacting a 9-(3,5-substituted-4-isoxazolyl)-7-hydroxyll -nonen-3-one of the formula "-41 or a tetrahydropyran-2-ol variant thereof of the formula lI-b with a 2-lower alkyl cycloalkane- 1,3-dione of the formula ill. The 3aB-alkyl-7-oxo-ll-lbenz[e]indenes and 8aB-alkyl-3H-phenanthren-Z-ones of the formula Xl are prepared by cyclizing the 4- or 5- (3-oxo-alkyl )-perhydroindene-5-ones and perhydronapthalene-6-ones of formula X which are obtained by oxidizing the pyrans of formula [-0. The latter perhydropyran intermediates are prepared by saturating the double bond of the diene of formula l-a and introducing R 0 (defined below) at the 4a-position and a hydrogen atom at the 9b-or l0a-position of monoene lb.

Alternatively, the compounds of formula Xl are prepared by alkylation (not shown in Reaction Scheme C) of a 3aB-alkyl-7-oxo-7H-benz[e]indene or 811B- alkyl-3l-I-phenanthren-2-one with a 3,5-disubstituted- 4-halomethyl isoxazole.

In Reaction Scheme C, Y is a substituted isoxazole of the formula lower primary alkyl or lower acyl; Z is selected from the group consisting of carbonyl, lower alkylenedioxymethylene, di-lower alkoxymethylene, phendioxymethylene and a group of the formula wherein R is selected from the group consisting of hydrogen, lower alkyl, lower alkoxy-lower alkyl, phenyl-lower alkyl, tetrahydropyranyl and lower acyl; R is selected from the group consisting of hydrogen and lower aliphatic hydrocarbyl; and m is an integer having a value from 1 to 2.

REACTION SCHEME C II-a OH (I? YCH2CHCH CHzCHzCCH=CH R1 0 R11 HO (8) (0H1)m 0 III YCHz- II-b R z RIZ I'I2)m HQm 5O :1

(w (b) (Ii (0) YCHWWK/ YCHZNW I-a T-b R R1 z 1 (0112)". (CH2)m R20 1-1 H o i/ \/i o ((1) H (e) 6 mama o X Y H l) wherein Y, R R R Z andm are defined aforesaid.

3 ,69 l 1 90 5 6 A still further aspect of this inv'iiho'n relates to the REACTION SCHEME D process and intermediate compounds employed to convert the benz[e']indenes and phenanthren-2-ones of v Rl z formula Xl in accordance with Reaction Schemes D (\om) and D to l9-nor-steroids of the formula XIV-a, 5 H J wherein R R R Z and m are as defined as H aforesaid and X is selected from the group consisting'of in-1f: H (g) \OARIU K n xv lower alkylenedioxymethylene, phendioxy-methylene, di-lower alkoxy-methylene, the monothia, monoaza or dithia chalcogen thereof and a group of the formula I a W R ing of carbonyl and a group of the formula z ZII EH91: unite." H H l R' is selected from the group consisting of hydrogen 5 R V and lower alkyl; Z is selected from the group consist- 1 OR xxv \RB 20 W is selected from the group consisting of carbonyl and R1 I Z f I (\Hflm agroupo the formula W M R H I W 0R1 H l r 3 Hm I H (i) Z" is selected from the group consisting of lower al- R" kylenedioxy-methylene, phendioxy-methylene, di- XXVI lower alkoxy-methylene, the monothia, monoaza or dithia chalcogen thereof anda group of tll e l:(El1l H 0 R1 l X 0R1 H 0 R15 H 2 m H v 4 Rs g R and R are defined as aforesaid; and R, is selected l (1) from the group consisting of hydrogen, lower alkyl', lower alkoxy-lower alkyl, .phenyl-lower alkyl and tetrahydropyranyl.

REACTION SCHEME D XXIX H o H I H l H m W H R15 0 O N xxvm x111 wherein W, R B R Z, R and m rgdefined aforesaid.

XIV-a wherein X, R R R Z, Z, R and m are defined aforesaid.

Yet another aspect of this invention relates to the conversion of, via novel intermediates, the benz[e]indenes and phenanthren-2-ones of the formula XI-a, in accordance with Reaction Scheme E, to the dienones of formula XXXV wherein R R', W, X, R Z, Z" and m are as defined aforesaid and V is selected from the group consisting of lower alkylenedioxy-methylene, di-lower alkoxy-methylene and phendioxy-methylene.

REACTION SCHEME E R z r H2)m r H l u N XI-a 2)ru (b) H H l i H v l O wV XXXI DBI (0) EN H H XXXII 2). O H H I l /\/\/\i/ 15 H y V XXXIII XXXV XXXVI wherein R W, Z, R,, R X, V, and m are as aforesaid.

DETAILED DESCRIPTION OF THE INVENTION As used throughout the specification and appended claims, the term hydrocarbyl group denotes a monovalent substituent consisting solely of carbon and hydrogen; the term hydrocarbylene denotes a divalent substituent consisting solely of carbon and hydrogen and having its valence bonds from different carbons; the term aliphatic", with reference to hydrocarbyl or hydrocarbylene groups, denotes groups containing no aromatic unsaturation, but which can be otherwise saturated or unsaturated, i.e., an alkyl or alkylene, or an aliphatic group containing olefinic or acetylenic unsaturation; the term alkyl group denotes a saturated hydrocarbyl group, whether straight or branched chain; the term primary alkyl group" denotes an alkyl group having its valence bond from a carbon bonded to at least two hydrogens; the term acyl group" denotes a group consisting of the residue of a hydrocarbyl monocarboxylic acid formed by removal of the hydroxyl portion of the carboxyl group; the termoxyhydrocarbyl" denotes a monovalent saturated cyclic or acylic group consisting of carbon, hydrogen, and oxygen containing only one oxygen in the form of an ether linkage and includes tetrahydropyranyloxy, and other alternate expressions such as lower alkoxy and lower alkoxy-lower alkyl; and the term lower, as applied to any of the foregoing groups, denotes a group having a carbon skeleton containing up to and including eight carbons, such as methyl, ethyl, butyl, tert.-butyl, hexyl, 2-ethylhexyl, vinyl, butenyl, hexenyl, ethinyl, ethylene, methylene, formyl, acetyl, 2-phenylethyl, benzoyl, methoxymethyl, lmethoxyethyl, tetrahydropyran-Z-yl and the like. The phraseology lower alkylenedioxy, the monothia, monoaza or dithia chalcogen thereof is used to indicate a ketalized 0x0 or thio moiety and comprehends moieties of the formula OR O, OR S,

OR N or SR S- wherein R is lower alkylene. Exemplary moieties are l,2-ethylenedioxy, 2,2-dimethyll,3-propylenedioxy, l,2-ethylenedimercapto, 2,3-butylenedioxy and the like. Phendiox denotes a dihydroxy aryl group such as catechol formed by removal of the hydrogen atoms from both hydroxyl groups. By the terms alkoxy and alkoxy-lower alkyl are meant alkyl and alkyloxy-lower alkyl groups such as methoxy, ethoxy, tertiary-butoxy, l-methoxy-ethyl, 2-ethoxyethyl and the like. The phraseology lower aralkyl denotes groups such as benzyl, l-phenylethyl, 4-phenylbutyl and the like. The term lower alkylaryl comprehends ethylphenyl, o-tolyl and the like. Halogen denotes all halogens, e.g., chlorine, fluorine, iodine, and bromine.

In the formulas presented herein, the various substituents on cyclic compounds are joined to the cyclic nucleus by one of three notations, a solid line indicating a substituent which is in the B-orientation (i.e., above the plane of the paper), a dotted line indicating a substituent which-is in the a-orientation (below the plane of the paper), or a wavy line indicating a substituent which may be in either the aor B-orientation. The formulas represented in Reaction Schemes C, D, D and E indicate the compounds in their racemic form except for the substituent defined by R which has been arbitrarily indicated as having the ,B-orientation. However, it will be appreciated that the synthesis described herein uniquely lends itself to the preparation of each of the compounds represented in the above-mentioned reaction schemes in its optically active form, in which case the indicated absolute configuration at C (steroid numbering) is that of naturally occurring steroids. The R and S designation of absolute stereochemistry employed herein is fully described in, RS. Cahn et al., Experientia 12, 81 (1956).

The preparation of the bicyclic compounds (X) is described in detail in copending U. S. application Ser. No. 778,314, as well as in accompanying Reaction Schemes A, B, and C.

The bicyclic compound (X) is treated with acid or base to effect cyclization to the tricyclic compound of formula (Xl) in accordance with Step (2) of Reaction Scheme C. ln this reaction, it is preferred that the water of reaction be removed when acidic conditions are employed as by refluxing the reaction mixture with an azeotroping agent and separating the water from the condensate. Suitable strong acids are sulfuric acid, ptoluenesulfonic acid, potassium bisulfate and the like. Alternatively, base catalyzed dehydration can be utilized, for example, by refluxing compound (X) in the presence of methanolic sodium hydroxide. It should be noted that when starting with a C/D-trans enol ether of the formula l-b, a trans-anti configuration will be obtained in the enone of the formula Xl, i.e., the C hydrogen (Steroid numbering) will be beta.

Alternatively, compounds of the formula Xl-b (EH1); H

O Riu XI-b can be prepared from l,2,3,3a,4,5,8,9,9a,9bdecahydro-3aB-alkyl-7-oxo-7H-benz[e]indenes and 4,4a,4b,a,9, l O-decahydro-8aB-alkyl-3H- phenanthren-Z-ones wherein the 6-and 1 positions respectively are substituted with hydrogen, by alkylation with a 4-halomethyl isoxazole. The reaction is suitably conducted in an organic solvent such as 1,2- dimethoxyethane, dimethylsulfoxide, or a lower alcohol, e.g., ethanol in the presence of a strong base such as an alkali metal alkoxide, e.g., sodium methoxide or an alkali metal hydride, e.g.,-sodium hydride. The reaction can be conducted at a temperature range of from room temperature to the reflux temperature of the solvent.

A further aspect of this invention relates to the process and intermediate compounds employed to convert the benz[e]indenes and phenanthren-Z-ones of formula Xl-a in accordance with Reaction Scheme D to l9-nor-steroids of the formula XIV-a.

The cycloolefin compounds of formula 'XI-a are hydrogenated to the tricyclic compounds of formula XV in accordance with Step (I) of Reaction Scheme D. The hydrogenation is preferably effected in a lower alcohol solvent, e.g., ethanol using a palladium metal catalyst and carbon carrier although other noble metal catalysts may be employed. The hydrogenation is conducted under neutral, acidic or weakly basic conditions substantially at atmospheric pressure and room temperature so as to selectively hydrogenate the A bond without substantially hydrogenating the isoxazolyl moiety. Suitable weak bases for this purpose are mono, di or tri-lower alkyl amines, preferably triethyl amine. It has been found that the use of base in this hydrogenation'step aides in selectively promoting the formation of the compound of formula XV which has a trans-anti-trans configuration when trans-anti enones of formula Xl-a are employed as reactants.

Use of aqueous hydrobromic acid, e.g., 0.003-10 mole equivalents of HBr with a 0.1-20 percent Pd/BaSO, catalyst in a lower alkanol, e.g., methanol or ethanol, in this hydrogenation step results in the promotion of the selective formation of the compounds of formula XV which have a trans-anti-cis configuration when the trans-anti-enones of formula XI-a are employed. In this reaction pressures of preferably about 1 atm. and a temperature of about room temperature may be conveniently employed.

The conversion of the tricyclic compounds of form ula XV to the steroids of formula XIV-a can be accomplished by three alternative reaction methods. Thus, process routes (1), (m), (o) and (k') hereinafter referred to as the heterocyclic anhydrous basic route and (l), (m'), (0") and (k') hereinafter referred to as heterocyclic aqueous basic route" exemplified in Reaction Scheme D can be employed. The third method is described in Reaction Scheme D.

At this point in the process, it should be noted that all hydrogenations conducted thus far viz, Steps (3) and (12) of Reaction Scheme B, Step (b) of Reaction Scheme C and Step (f) of Reaction Scheme D have been carefully conducted under mild hydrogenating conditions, i.e., in the absence of strong base and substantially at room temperature and atmospheric pressure to selectively avoid hydrogenating the isoxazole moiety to any significant degree. However, the isoxazole group can now be readily cleaved as described hereinafter.

The tricyclic compounds of formula XV can be converted to the l9-nor-steroids of formula XIV-a via the heterocyclic anhydrous basic route" which comprises sequential process Steps (1), (m), and (k) of Reaction Scheme D. Thus, the vinylogous amides of formula XXVII can be obtained from the tricyclic compounds of formula XV via Step (I), in the same reaction mixture that was employed to hydrogenate the compounds of formula Xl-a to the compounds of formula XV [Step (13], by the addition of strong base to the reaction medium and then further hydrogenating. Alternatively, hydrogenation of the isoxazole group of the isolated compound XV can be suitable conducted in the presence of a catalyst, preferably, a noble metal catalyst, such as rhodium, palladium, platinum, and the like or Raney nickel. The catalyst can be utilized with or without a carrier and if a carrier is used, conven-- tional carriers are suitable. Especially preferred is percent Pd/C. The ratio of catalyst to substrate is not critical and can be varied However, it has been found advantageous to use a weight ratio of catalyst to substrate from about 1:5 to about 1:25. Especially preferred is a ratio of 1:10. The hydrogenation is suitably effected in an organic atmospheric pressure in the presence of strong base, although higher temperatures and pressure may be employed. Preferred bases for the second hydrogenation are strong alkali metal hydroxides, e.g., potassium hydroxide, sodium hydroxide and the like. Treatment of the vinylogous amides of formula XXVll with anhydrous base, in accordance with Step (m) of Reaction Scheme D, results in dehydration and acyl cleavage of the compounds of formula XXVII to yield the dihydro pyridines of formula XXVllI. Preferred anhydrous bases for this conversion are alkali metal lower alkoxides, especially sodium ethoxide. The reaction is conveniently carried out in a lower alcohol solvent, preferably ethanol. Hydrolysis of the substituted dihydropyridines of formula XXVlll with aqueous alcoholic base in accordance with Step (0) of Reaction Scheme D yields the diketone compounds of formula XlIl'. Cyclization of the latter compounds, which are not isolable, occurs rapidly to give l9-nor-steroids of formula XlV-a in accordance with Step (k) of Reaction Scheme D.

It should be noted when employing the anhydrous basic route that the acyl group is selectively cleaved, thus enabling use of mixed isoxaxoles, e.g., those wherein R,,-, and R are not identical. This route thus permits obtention of uniform steroidal products viz those substituted at the steroidal C-4 position solely with an R' substituent.

l9-Nor-steroids of formula XIV-a can alternatively be obtained from the vinylogous amides of formula XXVlI via sequential process steps (m'), (0') and (k) viz, the heterocyclic aqueous basic route. The most significant difference between the heterocyclic aqueous basic route and the heterocyclic anhydrous basic route described immediately aforesaid, lies in the difference between process Steps (m) and (m'). In the former case, strong anhydrous base is employed in Step (m) yielding heterocyclic compounds of formula XX- VIII and in the later case strong aqueous base such as, for example, aqueous metal hydroxides, preferably WaOH, is employed in Step (m') yielding triketones of formula XXlX. It should be noted, however, that the aqueous basic route is not selective and probably also proceeds via Step (m) as well as Step (m'). The diketones of formula Xlll', which are obtained in accordance with Step (0') by cleaving the triketones of formula XXIX, further react by cyclizing (Step k) to yield steroids of formula XIV-a. The acyl cleavage effected in accordance with Step (0') is not selective, that is to say it is not possible to predict whether the group or the order to avoid the obtention of mixed steroidal I products. If either R or R is hydrogen, selective cleavage of the formyl group occurs, thus avoiding mixed steroidal products.

it should be emphasized as one further facet of the stereoselectivity of the instant invention, that when tricyclic compounds of formula XV having a trans-antitrans-configuration are employed in Reaction Scheme D, steroids of formula XlV-a having a trans-anti-transanti-configuration are produced. This is highly desirable since many pharmacologically valuable compounds possess this configuration.

Furthermore, when tricyclic compounds of formula XV having a trans-anti-cis configuration are used in Reaction Scheme D, steroids of formula XIV-a having a trans-anti-cis-anti-configuration are produced. These compounds are l9-nor-9,8,l0a-steroids which are also known as l9-nor-retrosteroids and form a further class of pharmacologically valuable compounds.

In compounds represented by the formulas XXVII, XXVlII and Xlll' of Reaction Scheme D, Z is defined in an identical manner to Z as defined aforesaid, with the proviso that Z can not be a lower alkylenedioxymethylene, phendioxy-methylene or dialkoxymethylene or ester function. However, the endproducts of formula XIV-a substituted in the l7-position (steroidal numbering) by Z are obtained from the precursors of the formulas which are substituted in the l7-position by Z by means known in the art.

When effecting the conversion of benz[e]indenes and phenanthren-Z-ones of formula Xl-a to the steroids of formula XIV-a via either the heterocyclic aqueous basic group or the heterocyclic anhydrous basic group in accordance with Reaction Scheme D, variable amounts of pyridines are produced even when oxygen is excluded from the reaction medium. These pyridine products presumable arise from oxidation or disproportionation of some of the intermediates.

Therefore, another aspect of this invention relates to the process and intermediate compounds employed to convert the tricyclic compounds of formula XV to the steroids of formula XIV-a in accordance with Reaction Scheme D via process Steps (g), (h), (i), (j) and (k) which avoids the formation of pyridine intermediates and thereby correspondingly raises the yield of steroids produced. Pyridine formation is avoided in accordance with teachings of this invention by preventing cyclization to the vinylogous amides of formula XXVII (Reaction Scheme D) by first protecting the 7-position of the tricyclic compounds of formula XV prior to hydrogenating the isoxazole moiety.

The protected compounds of formula XXV are obtained from the tricyclic compounds of formula XV in accordance with Step (g) of Reaction Scheme D by converting the free oxo group of the compounds of formula XV to a group represented by Z" as defined aforesaid. This protection can be effected by ketalization to form the phendioxy-methylene, lower alkylenedioxy-methylene, di-lower alkoxy-methylene, or the monothia, monoaza, or dithia chalcogen thereof by means known in the art. Preferred ketals are 1,2- ethylenedioxy, 2,3-butylenedioxy, and 2,2-dimethyll,3-propylenedioxy which can be obtained by reaction of the compounds of formula XV with the corresponding alcohols in a known manner. Alternatively, the x0 moiety can be converted to its dithia ketal by reaction with dithioethane in a known manner, for example, in acetic acid at room temperature and in the presence of boron trifluoride. Moreover, a monothia ketal can similarly be prepared in a known manner, for example, by reaction of the 0x0 moiety with Z-mercaptoethanol in dioxane at room temperature in the presence of zinc chloride and sodium sulfate. Also, the monoaza ketals can be prepared in a known manner, for example, by reaction of the 0x0 moiety with Z-hydroxyethylamine in the presence of acid.

Further, the oxo moiety can be reduced to the corresponding hydroxy compound with for example, sodium borohydride at low temperature and can then be etherified or esterified. A preferred ether protecting group is tertiarybutoxy which can conveniently be obtained from the corresponding hydroxy derivative by reaction under acid conditions with isobutylene' by means known in the art.

The oxo moiety can be regenerated from its protected form at any desired stage of the reaction sequence. Thus, it can be readily produced by hydrolysis of the alkylenedioxy ketals in a known manner. Similarly, it can be regenerated from the dithia ketal in a known manner, for example, by treatment with phenylmercuric chloride and calcium carbonate in ethanol or by treatment with methanolic hydrochloric acid. Also, it can be regenerated from a monothia ketal in a known manner, for example, by treatment under strongly acidic conditions, for example, by treatment with aqueous sulfuric acid in dioxane or hydrochloric acid in acetic acid. Moreover, it can be regenerated from a monoaza ketal in a known manner, for example, by treatment with a strong aqueous acid. Also, ethers and/or esters can be reconverted to the free hydroxy group which in turn can be oxidized to give the 0x0 moiety.

The protected compounds of formula XXV are hydrogenated in accordance with .Step (h) of Reaction Scheme D to yield the vinylogousamides of formula XXVI. The hydrogenation is conducted under process conditions suitable to hydrogenate the isoxazolyl groups. A catalyst, preferably a noble metal catalyst, such as platinum, palladium and the like or Raney nickel or the like is employed. Especially preferred is the palladium catalyst. The noble metal catalyst can be utilized with or withoutla carrier and if a carrier is used, conventional carriers are suitable. It is preferred to use palladium on carbon. Especially preferred is 10 percent Pd/C. The ratio of catalyst to substrate is not critical and can be varied. However, it has been found advantageous to use a weight ratio of catalyst to substrate from about l:5 to 1:25. Especially preferred is a ratio of 1:10. The hydrogenation is suitably effected in the presence of strong base, preferably an alkali metal hydroxide, e.g., potassium hydroxide in an inert or ganic solvent for example, lower alcohols, e.g., methanol, ethanol or isopropanol. The reaction conditions of pressure and temperature are not narrowly critical as is the case when it is desired to avoid hydrogenating the isoxazole moiety. Therefore, if desired, pressures above one atmosphere and temperatures above room temperature may be suitably employed.

The vinylogous amides of formula XXVI are hydrolyzed to the diketones of formula XXX in accordance with Step (i) and cleaved in accordance with Step (i) of Reaction Scheme D to yield the ketones of formula XIII using aqueous alkali hydroxide, preferably sodium hydroxide. The acyl cleavage effected in accordance with Step (1) is not selective. It is not possible to predict whether the group or the group will be cleaved. It is, therefore, desirable when employing this route that R and R be selected so as to be identical or in the alternative either R or R be hydrogen to avoid the obtention of mixed steroid products. It should be noted, that if the function at position C-1 7 (steroid numbering) is an ester, it will be cleaved to the free alcohol under the conditions employed in Steps (1') and (j).

Treatment of the ketone of formula XIII wherein Z" is a ketal function with a mineral acid, preferably hydrochloric acid in a lower alcohol solvent, suitably methanol at reflux, yields the steroids of formula XIV-a via Step (k) of Reaction Scheme D by a process sequence of removal of the protecting group and cyclization. For cases wherein the protecting group Z" of the ketone of formula XIII is other than a ketal function, the group is first removed and the free carbonyl group'is regenerated by known methods, e.g., in the case of an alcohol with an oxidizing agent such as Jones reagent, prior to cyclization (Step k).

It should be noted that the process steps carried out in Reaction Scheme D are stereoselective viz if the .tricyclic compounds of formula XV have a trans-antitrans-configuration the steroid products of formula XIV-a have a trans-anti-trans-anti-configuration while if the tricyclic compounds of formula XV have a trans-anti-cls configuration the steroid products of formula XIV-a have a trans-anti-cis-anti-configuration.

In compounds represented by formulas XXV, XXVI and XIII of Reaction Scheme D, Z is defined in an identical manner to Z, as defined aforesaid, with a proviso that 2" cannot be a a free carbonyl function. However, the end products of formula XIVa substituted in the l7-position by Z are obtained from the precursors of formula XIV-a which are substituted in the l7-position by Z" by means known in the art.

Still another aspect of this invention relates to the process and intermediate compounds employed to convert the benz[e]indenes and phenanthren-Z-ones of the formula XI-a in accordance with Reaction Scheme E to the estrones of the formula XXXVI.

The enones of formula XI-a are converted to the protected A -compounds of formula XXXI in accordance with Step (a) of Reaction Scheme E, wherein R,, R, R Z, Z, W, V and m are defined as aforesaid. Protection can be effected by ketalization of the free carbonyl group of the compound of the formula XI-a via methods previously described (Step g, Reaction Scheme D). Preferred ketals are 1,2- ethylenedioxy, 2,3-butylenedioxy, 2,2-dimethyl-l,3- propylenedioxy and the like. As is evident from the structure of compounds of formulas Xla and XXXI ketalization results in isomerizing the A -unsaturated compounds to the A ""-unsaturated compounds.

The protected compounds of formula XXXI are hydrogenated in accordance with Step (b) to yield the A "-vinylogous amides of formula XXXII. The hydrogenation is conducted under identical conditions employed for the hydrogenation in accordance with Step (h) of Reaction Scheme D. Unexpectedly, it has been found in accordance with the teachings of this invention that the hydrogenation of the compound of formula XXXI is selective, that is only the isoxazole moiety is hydrogenated without hydrogenating the A -unsaturated bond to any significant degree.

The resulting vinylogous amide of formula XXXII is treated as before, e.g., Steps (1') and (j) of Reaction Scheme D with aqueous alkali metal hydroxide base to yield the A -ketones of formula XXXIII. The A diketones of formula XXXIV are obtained from the A -ketones of formula XXXIII in accordance with Step (d) of Reaction Scheme E by treatment with aqueous mineral or organic acid, preferably acetic acid at a temperature range of 50 C. to the reflux temperature of the solvent.

The diketo A -compounds of formula XXXIV can be converted to the A A -steroids of formula XXXV. In a specific embodiment, the diene of formula XXXV, wherein Z is carbonyl, R', is hydrogen, R, is methyl and m is 1 can be isomerized to the pharmaceutically valuable compound of formula XXXVI (estrone) via Step (f) of Reaction Scheme E if the transanti-steroisomer of formula XI-a is used as a starting reactant. These methods of Steps (e) and (f) are more fully described in French Pat. No. 1,305,092, assignee Roussel-Uclaf.

The compound of formula XIV-a, Reaction Scheme D wherein Z is carbonyl, m is l, R, is ethyl and R,, is hydrogen l9-norl 8-homo-androst-4-ene-3, l 7- dione), can be selectively alkynylated by a suitable organo metallic acetylide affording norgestrel (13B- ethyl-17a-ethinyl-l7-hydro'xy-gon-4-ene-3-one), a known progestational agent. Exemplary of the suitable alkynylating agents to effect the conversion to norgestrel are the alkali acetylides such as lithium acetylide, potassium acetylide, sodium acetylide and the like. The reaction is carried out in the presence of liquid ammonia in a suitable solvent system such as benzene or toluene. The alkynylation is effected preferably at the reflux temperature of the reaction medium although temperatures from 60 C. to 30 C. are suitable. Exemplary of other suitable reagents to effect the acetylenic addition is lithium acetylide diamine complex in dimethylformamide as solvent.

Compounds of formula XIV-a wherein Z is carbonyl can be converted into corresponding pharmaceutically valuable known pregnane compounds i.e., compounds of which Z is of the formula:

by known procedures. (Cf., US. Pat. No. 3,383,385, Bucourt et al.). These procedures for converting androstan-l7-ones into pregnanes are best effected if all carbonyl groups other than that at C-l 7 are initially protected. Thus, for example, 19-nor-14/3-androst-4- ene-3,l7-dione can be converted into l9-nor-l4B-l 7aprogesterone.

The l9-nor-compound of formula XIV-a, Reaction Scheme D wherein m is l, R, is propyl and R,, is hydrogen are ovulatory inhibitors [cf., Tetrahedron Letters, 127 (I961), Velluz et al.]. Additionally, compounds of formula XIV-a wherein R, is methyl, R,, is hydrogen, m is l and Z is carbonyl have been converted to l9-nor-testosterone acetate, J. Org. Chem., 26, 3904 (1961), L. J. Chinn et al.

Compounds of formula XIV-a of Reaction Scheme D having the trans-anti-cis-anti configuration have been described in the literature. Thus racemic l9-nor- 9,8,10a-androst-4-en-3,l7-dione (Z is carbonyl, m is l, R, is hydrogen and R, is methyl) is disclosed by Torgov et al., Chemistry of Natural Compounds, 1, 138 (1965). Optically active l9-nor-9B,lOatestosterone (Z is hydroxymethylene, m is l, R',, is hydrogen and R, is methyl) was described by Velluz et al., Comptes Rendues, 252, 3903 (1961) while the l7a-methyl derivative of this compound is described by Farkas et al., J. Org. Chem, 34 3022 (1969).

As has been pointed out above, the products of this invention are produced in the form of various optically active antipodes, which can be carried through the entire reaction sequence, or which can be resolved at suitable places during the reaction sequence. For example, at any stage wherein a compound having a secondary hydroxyl group is present, one can react the secondary alcohol with a dicarboxylic acid to form a half ester. Suitable dicarboxylic acids include lower alkyl dicarboxylic acids such as oxalic acid, malonic acid, succinic acid, glutamic acid, adipic acid, or aromatic carboxylic acids such as phthalic acid. The

mm" mm resulting half-ester is then reacted with an optically active base, such as brucine, ephedrine, or quinine, to produce a diastereomeric salt. The salts, after separation, are then readily reconverted to optically active alcohols. As an alternative, the secondary alcohol can be reacted with an optically active acid, for example, camphorsulfonic acid. The resulting diastereomeric esters are then separated and reconverted to the alcohols.

It is preferred that the resolution be effected at some stage in the synthesis of the compounds of formulas ll-a, Ila-l or lI-b as by the resolutions heretofore described. Resolution at such early stages in the overall process described herein is highly preferred because of the improved efficiency in the production of steroids having a desired configuration. Because the condensation of the alken-3-one or variant (ll-al ll-a 'or lI-b) with cycloalkanedione (III) is stereo-specific, as are the subsequent reaction steps, one, by proper selection of stereoisomers at these early stages, can ensure that substantially all of the tricyclic compounds of this invention and the steroids derived therefrom have a selected configuration. Thus, by this technique, the production of compounds of the undesired configuration is minimized or prevented entirely, with an attendant increase in the efficiency of the production of compounds of the desired configuration.

A further aspect of the present invention relates to novel l9-nor-retrosteroids of the formula XXXVI where R is lower alkyl with at least two carbon atoms.

Compounds of formula XXXVlI are anabolic, androgenic agents with a favorable anabolic/androgenic ratio. They are pituitary inhibitors, anti-estrogenic and lower cholesterol level in blood. 7

In the claims, all compounds should be construed to include, independently, the racemic form of the compound and independently each enantiomeric form unless specifically indicated otherwise.

The following examples are illustrative but not limitative of the invention. All temperatures are stated in degrees centigrade. Infrared, ultraviolet and nuclear magnetic resonance spectra where taken were consistent with exemplified structures.

EXAMPLE 1 Preparation of 4-carboethoxy-3,S-dimethylisoxazole A solution of 320 ml. (325 g. 2.5 moles) of ethyl acetoacetate, 209 ml. (178g. 2.5 moles) of pyrrolidine and 600 ml. of reagent grade benzene was heated at reflux with azeotropic removal of water for 2 hours. The benzene was then removed at reduced pressure and the residue was distilled through a l-cm. Vigreux column yielding 427 g. of ethyl fl-pyrrolidineocrotonate as a light yellow liquid, b.p. l55l 5 6/- 10 mm.

A solution of the ethyl l3-pyrrolidinocrotonate (427 g. 2.33 moles), 190 ml. (182 g., 2.43 mole) of nitroethane and 1,300 m1. of triethylamine in 1,200 ml. of anhydrous chloroform was cooled in an ice bath under nitrogen. A solution of 235 ml. (393 g. 2.56 mole) of phosphorous oxychloride in 400 ml. of chloroform was added at such a'rate that the temperature did not rise above 15. During the addition, which took place over a 3-hour period, a viscous orange precipitate formed. This suspension was then stirred under nitrogen overnight. As much solvent as possible was removed at reduced pressure and the resulting redbrown paste was diluted with water and extracted with ether. The ether solutions were washed sequentially with water, 3N hydrochloric acid, water, 5 percent sodium hydroxide solution and water, and were dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a dark oil which was distilled through a short Vigreux column to give 4-carboethoxy- 3,5-dimethylisoxazole as a slightly cloudy, colorless liquid of b.p. l00/l 1 mm.

EXAMPLE 2 Preparation of 3,5-dimethyl-4-hydroxymethylisoxazole A suspension of I00 g. (2.63 moles) of lithium aluminum hydride in 2.5 liters of anhydrous ether was stirred under nitrogen as a solution of 272 g. (1.61 mole). of the 4-carboethoxy-3,S-dimethylisoxazole prepared in Example 1 above in 400 ml. of anhydrous ether was added at such a rate as to maintain a gentle reflux. The suspension was stirred at room temperature under nitrogen overnight, during which time an extremely gummy greemgray mass formed in the bottom of the flask. The mixture was cooled in an ice bath and hydrolyzed with saturated aqueous sodium sulfate solu- .tion. Anhydrous sodium sulfate was added to dry the ether solution. The salts were removed by filtration and washed carefully with ether and chloroform. Solvent removal from the filtrates, finally at 50/0.l mm., gave a white crystalline mass. This was triturated with hot ether and then cooled. Filtration gave 3,5-dimethyl-4- hydroxymethyl-isoxazole as white prisms, m.p. 76.5-7 7.5. Concentration of the mother liquors gave a second crop of prisms, m.p. 76.578.

EXAMPLE 3 EXAMPLE 4 Preparation of (3 ,5-dimethyl-4-isoxazolylmethyl )triphenyl-phosphonium chloride A solution of 59.6 g. (0.402 mole) of '4- chloromethyl-3,S-dimethylisoxazole, prepared as described above, and H6 g. (0.44 mole) of triphenylphosphine in 1 liter of toluene was heated at reflux under nitrogen for 6 hours. The resulting suspension was cooled and filtered. The filtrate was heated at reflux for an additional 20 hours. The precipitate was again removed by filtration and the combined solids were washed well with ether and benzene. The solvent was removed from the filtrate and the residue was taken up in 150 ml. of fresh toluene and refluxed for an additional 18 hours. Filtration as before gave another small quantity of solid. The combined solids were crystallized from ethanol-ether to give the desired phsophonium salt as a cream-white solid, m.p. 313-31 6.

A sample from a similar preparation was crystallized again from ethanol-ether to give analytically pure material as small white prisms, m.p. 303-305. (The melting point of this compound is dependent on the rate of heating.)

Anal. Calcd. for C ,H ClNOP: C, 70.67; H, 5.68; Cl, 8.69; N, 3.44; O, 3.92; P, 7.60. Found: C, 70.73; H, 5.69; N, 3.55; Cl, 8.66.

EXAMPLE Preparation of racemic 3,5-dimethyl-4-(3,4-dihydro- 2H-pyran-2-ylvinyl) isoxazole 8.75 G. (0.20 mole) of 55 percent sodium hydride dispersion was washed under nitrogen with dry pentane to remove the mineral oil. To the flask was added 600 ml. of dimethylsulfoxide (dried over Linde 3A molecular sieves). The resulting suspension was carefully degassed, placed under nitrogen, and heated at 7075 for 1 hour. The gray-green solution was cooled to approximately and 91.6 g. (0.20 mole) of (3,5- dimethyl-4-isoxazolylmethyl)triphenylphosphonium chloride, prepared as described in Example 4 above, was added in one portion. After approximately 5 minutes, a bright orange precipitate formed in the initially dark red solution. This suspension was stirred at room temperature for 45 minutes. To the mixture was then added, drop-wise via syringe, 25.0 g. (0.223 mole) of acrolein dimer (freshly distilled from and into hydroquinone) at such a rate that the temperature remained less than 30 (10-15 minutes with water bath cooling). The light orange-brown solution was stirred at room temperature for minutes, and then at 6065 for 3 hours. (In some experiments, the mixture became very black during the heating period). The reaction mixture was cooled, poured onto ice, and slurried until all of the dark oil solidified. The suspension was filtered and the filter cake was washed well with pentane. The filtrates were extracted with pentane and the pentane solutions were washed with water and brine and dried over anhydrous sodium sulfate. Solvent removal gave a slightly orange oil which was distilled from a small quantity of anhydrous potassium carbonate to give the-desired product as a colorless liquid,

b.p. 83-85/0.l mm. A similarly prepared sample of EXAMPLE 6 Preparation of racemic 7-(3,5-dimethyl-4-isoxazolyl)- s-hydroxy-A -heptenoic acid lactone To a solution of 33.5 g. (0.163 mole) of 3,5- dimethyl-4-( 3 ,4-dihydro-2l-l-pyran-Z-ylvinyl) isoxazole, prepared as described in Example 5 above, in 400 ml. of dioxane, was added 400 ml. of 1N sulfuric acid and the cloudy solution, which soon cleared, was stirred at room temperature for 1 hour. The mixture was poured into 2 liters of saturated aqueous sodium bicarbonate solution and extracted well with ether. The ether extracts were washed with brine and dried over anhydrous sodium sulfate. Solvent removal gave a colorless oil, the infrared spectrum of which indicated that complete hydration of the enol ether had taken place. This material was taken up in 2 liters of benzene and placed under nitrogen. To the flask was added 400 g. of manganese dioxide and the resulting suspension was stirred at room temperature for 40 hours. The manganese dioxide was removed by filtration and carefully washed with fresh benzene. Solvent removal from the filtrate gave 23 g. of yellow solid. Two crystallizations of this material from benzene-ether gave the desired lactone as a cream-white powder, m.p. 90.0-9 1.5. A sample from a similar preparation was crystallized again from the same solvent pair to give analytically pure material as fine white needles, m.p. 9l-92.5.

Anal. Calcd. for c u no C, 65.14; H, 6.83; O, 21.70; N, 6.33. Found: C, 64.93; H, 6.71; N, 6.06.

EXAMPLE 7 Preparation of racemic 7-(3,5-dimethyl-4-isoxazolyl)- 5-hydroxyheptanoic acid lactone A. From racemic 7-(3,5-dimethyl-4-isoxazolyl)-5- hydroxy-A -heptenoic acid lactone A mixture of 16.80 g. (76.0 mmoles) of racemic 7- (3,5-dimethyl-4-isoxazolyl)-5-hydroxy- A -heptenoic acid lactone, 400 ml. of ethyl acetate, and 500 mg. of 10 percent palladium on carbon was hydrogenated at room temperature and atmospheric pressure. Uptake 1.25 X theoretical) was rapid and ceased after 2 hours. The catalyst was removed by filtration and washed with fresh ethyl acetate. Solvent removal gave a colorless oil which was crystallized from ether at -20 to give the desired product as white microprisms, m.p. 59-62. A small portion of a similarly prepared sample was crystallized again from ether to give white microprisms of m.p. 6 l62.5, )t,,,,, 220 p. (e 5350).

Anal. Calcd. for C I-1 N0 1 C, 64.55; H, 7.68; O,

21.50; N, 6.27. Found: C, 64.59; H, 7.77; N, 6.12.

B. From 3,5-dimethyl-4-(3,4-dihydro-2H-pyran-2-ylvinyl) isoxazole.

To a solution of 1.0 g. (4.88 mmoles) of 3,5- dimethyl-4-( 3 ,4-dihydro-2H-pyran2-ylvinyl) isoxazole, prepared as described in Example 5 above, in 10 ml. of ethanol was added five drops of 1N sulfuric acid. The solution was stirred at room temperature overnight, poured into excess saturated aqueous sodium bicarbonate solution, and extracted with ether. The ether extracts were washed with water and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave 1.25 g. of pale yellow liquid whose infrared spectrum indicated that formation of racemic 3,5-dimethyl4-(6-ethoxytetrahydropyran-2 ylvinyl)isoxazole was complete. This material was taken up in 10 ml. of ethyl acetate. To this solution was added 25 mg. of 10 percent palladium on carbon and the resulting mixture was hydrogenated at room temperature and atmospheric pressure. After 2 hr., one equivalent of hydrogen had been consumed and uptake ceased. The catalyst was removed by filtration and washed with fresh ethyl acetate. Solvent removal from the filtrates gave 1.28 g. of racemic 3,5-dimethyl-4-(6-ethoxytetrahydropyran-Z-ylethyl)-isoxazole as a colorless oil whose infrared spectrum indicated that the hydrogenation was complete. This crude acetal was taken up in 20 ml. of dioxane. To the flask was added 10 ml. of 1N sulfuric acid and the resulting solution was stirred at room temperature for 4 hr. It was then poured into excess saturated aqueous sodium bicarbonate solution and extracted with ether. The ether extracts were washed with saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave racemic 3,5-dimethyl-4- (6-hydroxytetrahydropyran-2ylethyl)-isoxazole as a viscous oil. The crude hemiketal was taken up in 25 ml. of 1,2-dichloroethane, degassed and placed under nitrogen. To the flask was added 7.5 g. of manganese dioxide and the resulting suspension was stirred at room temperature overnight. The manganese dioxide was removed by filtration and washed with fresh solvent. Solvent removal from the filtrates gave a pale yellow resin which was crystallized from ether at 20C. to give the desired acetone as a white solid of m.p. 60-62. A similarly prepared sample was shown by its infrared and nmr spectra, mixture melting point, and thinlayer chromatographic behavior to be identical with the material prepared as described above input A.

C. Via Racemic 7-(3,5-dimethyl-4-isoxazolyl)-5- oxo-heptanoic acid A solution of 3,5-dimethyl-4-(6-hydroxytetrahydropyran-Zylethyl)-isoxazole, prepared as described in part B from 60.5 g. (0.294 mole) of racemic 3,5-dimethyl-4-(3,4-dihydro-Zl-Lpyran-Z-ylvinyl)-isoxazole, in 600 ml. of acetone was cooled in an ice bath as 400 ml. of Jones reagent was added dropwise over a 1.0 hr. period. The resulting suspension was stirred at room temperature overnight. Saturated sodium bisulflte solution was added to destroy the excess oxidizing agent and most of the acetone was removed at reduced pressure. The residue was diluted with water, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and then with excess saturated aqueous sodium bicarbonate solution. The sodium bicarbonate solutions were washed with ether, acidified with 3N hydrochloric acid, saturated with sodium chloride, and extracted with ethyl acetate. The ethyl acetate solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a pale yellow resin. Crystallization of this material from ether gave two crops of racemic'7-(3,5- dimethyl-4 -isoxazolyl)-5-oxo-heptanoic acid as a fine white powder, mp. 61 .563,5.

Anal. Calcd. for C H NO,: C, 60.24; H, 7.16; N, 5.85. Found: C, 60.15; H, 7.29; N, 5.78.

A solution of the keto acid prepared above (41.2 g., 0.173 mole) in 600 ml. of isopropyl alcohol was placed under nitrogen. To this solution was carefully added 10.0 g. (0.296 mole) of sodium borohydride. After the initial vigorous reaction had subsided, the cloudy solution was heated at reflux overnight. A major portion of the solvent was then removed at reduced pressure. The

residue was diluted with water, acidified with 1N hydrochloric acid, saturated with salt, and extracted with ether. The ether solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave racemic 7-(3,5- dimethyl-4-isoxazolyl)S-hydroxyheptanoic acid as a cloudy colorless resin. This material was heated to 220/0.3 mm., at which time a colorless liquid rapidly distilled. Crystallization from ether gave the desired lactone as white prisms, m.p. 6l63.

EXA PLE 8 Racemic-3-[ 2-( 3 ,5-dirnethyl-4-isoxazolyl )ethyl]-6aB- methyl 1 ,2,3,5,6,6a-hexahydrocyclopenta[f][ 1 ]benzopyran-7(8H)-one A. A solution of 10.0 g. (44.8 mmoles) of racemic 7- (3,5-dimethyl-4-isoxazolyl)-5hydroxyheptanoic acid lactone, prepared as described in Example 7 above, in 150 ml. of freshly distilled tetrahydrofuran was cooled in a dry ice-isopropyl alcohol bath under nitrogen. A 25 percent (weight/volume) solution of. vinyl magnesium chloride in tetrahydrofuran (25 ml., mmoles) was added via syringe at a rate such that the temperature remained at approximately 60. The mixture was stirred at -70 for 15 min., and then carefully hydrolyzed with 5 ml. of methanol. It was then poured onto ice, 24 g. of ammonium chloride, and 8 ml. of acetic acid. The resulting solution was extracted with ether and the ether solutions were washed with water, saturated aqueous sodium bicarbonate solution, and saturated brine and dried over anhydrous sodium sulfate. After 10 minutes, 10 ml. of diethylamine was added to the ethereal solution of racemic 9-(3,5- dimethyl-4'isoxazolyl)-7-hydroxynon-1en-3-one. Ten minutes later, solvent removal gave crude racemic 2- (2-diethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]tetrahydropyran-2-ol as a light yellow oil. This material was taken up in ether and extracted with a total of ml. of 1N hydrochloric acid followed by 25 ml. of water. The aqueous solutions were washed with ether and then placed under a layer of ether in an ice bath. The solution was made basic with 3N sodium hydroxide and then extracted with ether. The ether extracts were washed with water and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave the Mannich base as a pale yellow oil.

A- solution of 5.3 g. (47.2 mmoles) of 2-methylcyclopentane-l,3 -dione in 150, ml. of toluene and 50 ml. of acetic acid was carefully degassed, placed under nitrogen and heated at reflux for 5 minutes. A solution of the Mannich base prepared above in 50 ml. of toluene was added and refluxing was continued for 2 hr. The cooled solution was washed with water, saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave a reddish-orange gum which was filtered through g. of Woelm neutral alumina, activity grade Ill. Elution with benzene brought off a light pink band followed by a yellow band. Solvent removal from the eluent gave the desired dienol ether as a light orange crystalline solid.

A sample of this product was crystallized from etherhexane and then from ether at -20 to give analytically pure racemic 3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]- 6aB-methyl-l,2,3,5,6,6a-hexahydrocyclopenta[f][1 benzopyran-7(8H)-one as light yellow prisms of m.p. ll3-l 16.

Anal. Calcd. for C H NO C, 73.36; H, 7.70; N, 4.28; O, 14.66. Found: C, 73.64; H, 7.72; N, 4.57.

B. To a solution of 20.0 g. (89.6 mmoles) of racemic 7-( 3 ,5 dimethyl-4-isoxazolyl )-5-hydroxy heptanoic acid lactone, prepared as described in Example 7 above, in 100 ml. of dry toluene, which had been cooled to 70 C. under nitrogen, was added 95 ml. of a 20 percent solution of diisobutylaluminum hydride dropwise ober a period of three-fourths hour. The mixture was stirred 1 hour at 70 C., and then hydrolyzed in the cold with 80 ml. of 6 N sulfuric acid. After the solution had warmed to room temperature, the layers were separated and the organic solutions were washed with water, saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave racemic 3,5-dimethyl-4-(6-hydroxytetrahydropyran-2- ylethyl)isoxazole as 18.1 g. of colorless viscous oil.

In a previously dried flask, 200 ml. of a l M solution of vinyl magnesium chloride in tetrahydrofuran was stirred at room temperature as a solution of the hemiacetal prepared above (alternatively, hemiacetal prepared as described in Example 7 may be used) in 50 ml. of tetrahydrofuran was added at such a rate that the temperature remained less than 35. The mixture was stirred at room temperature overnight and then hydrolyzed by pouring onto ice and ammonium chloride. Extraction with ether, washing the ether solutions with brine, drying over anhydrous sodium sulfate, and solvent removal gave racemic 9-(3,5-dimethyl-4- isoxazolyl)-non-l-en-3,7-diol as a viscous colorless resin.

To a solution of the diol prepared above and 0.25 g. of hydroquinone in 600 ml. of l,2-dichloroethane was added 120 g. of manganese dioxide. The resulting slurry was stirred 6 hours at room temperature before the manganese dioxide was removed by filtration. The filter cake was washed well with fresh chloroethane and the combined filtrates were concentrated to 500 ml. To this solution of racemic 9-(3,5- dimethyl-4-isoxazolyl)-7-hydroxy non-l-en-3-one was added 10 ml. of diethylamine. After one-half hour, solvent removal at reduced pressure gave crude racemic 2-(2-diethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]tetrahydropyran 2-ol as a light yellow oil. This material was taken up in either and extracted with a total of 100 ml. of 1N hydrochloric acid followed by 25 ml. of water. The aqueous solutions were washed with ether and then placed under a layer of ether in an ice bath. The solution was made basic with 3N sodium hydroxide and then extracted with ether. The ether extracts were washed with water and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave the Mannich base as a pale yellow oil.

A solution of 5.3 g. (47.2 mmoles) of Z-methylcyclopentane-l,3-dione in 150 ml. of toluene and 50 ml. of acetic acid was carefully degassed, placed under nitrogen and heated at reflux for 5 minutes. A solution of the Mannich base prepared above in 50 ml. of toluene .was added and refluxing was continued for 2 hours. The cooled solution was washed with water, saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave a reddish-orange gum which was filtered through 150 g. of Woelm neutral alumina, activity grade III. Elution with benzene gave dienol ether spectrally identical with the material prepared in part A as a pale orange solid.

EXAMPLE 9 Preparation of racemic trans-anti-6-[(3,5-dimethyl-4- isoxazolyl)-methyl]-3a-methyll ,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e) indene-3.7(8H)-dione A suspension of 1.60 g. (41 mmoles) of lithium aluminum hydride in 150 ml. of freshly distilled tetrahydrofuran was cooled under nitrogen in an ice bath as a solution of 12.0 g. of the dienol ether racemic 3-[2-(3,5dimethyl-4-isoxazolyl) ethyl]6aB-methyll,2,3,5,6,6a-hexahydrocyclopenta[f][ l ]benzop-yran- 7(8H)-one, the preparation of which is described in Example 8, in 50 ml. of tetrahydroguran was added over 10 minutes. The suspension was stirred at 0 for another 10 minutes and then at room temperature for one-half hr. The mixture was cooled again in an ice bath, carefully hydrolyzed with saturated aqueous sodium sulfate solution, and dried over anhydrous sodium sulfate. The salts were removed by filtration and washed with fresh tetrahydrofuran and chloroform. Solvent removal from the filtrates gave a cream-white solid. Normally the hydroxy dienol ether thus obtained was used without further purification. However, the material from one experiment was crystallized from ethertetrahydrofuran and then from tetrahydrofuran to give analytically pure racemic 3-[2-(3,5-dimethyl-4- isoxazolyl)ethyl]-6a,B-methyl-l ,2,3,5 ,6,6a,7,8-octahydrocyclopenta[f][ l ]benzopyran-7B-ol, as a creamwhite crystalline powder, m.p. l58.5l65.

Anal. Calcd. for C H NO C, 72.92; H, 8.26; O, 14.57; N, 4.25. Found: C, 73.22; H, 8.26; N, 4.03.

The crude hydroxy dienol ether prepared above was dissolved in 350 ml. of freshly distilled tetrahydrofuran. To this solution was added 750 mg. of a 5 percent palladium on carbon catalyst and the resulting mixture was hydrogenated at atmospheric pressure and room temperature. Uptake of one equivalent of hydrogen took 4 hours. The catalyst was removed by filtration and washed with fresh tetrahydrofuran. Solvent removal gave racemic trans-3-[2-(3,5-dimethyl-4-isoxazolyl)ethyl]-6a-methyll ,2,3,5,6,6a,7,8,9,9adecahydrocyclopenta[f][ l ]benzopyran-7B-ol as a pale green resin. v

A solution of the hydroxy enol ether trans-3-[2-(3 ,5- dimethyl-4-isoxazolyl)ethyl]-6a-methyl-l ,2,3 ,5,6,6a, 7,8,9,9a-decahydrocyclopenta[f][ l]benzopyran-7B-ol prepared above in 250 ml. of acetone was stirred at room temperature with ml. of 1N sulfuric acid for l /2 hr., during which time the solution became light pink in color. This solution was carefully poured into excess saturated aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal gave racemic trans-3- [2-( 3 ,5 dimethyl-4-isoxazolyl)ethyl] -6a-methyl-p erhydrocyclopenta[f][ l ]benzopyran-4a,7B-diol as a yellow resin. The infrared spectrum of this sample showed that complete hydration of the enol ether had occurred.

A solution of the hemiketal trans-3-[2-(3,5- dimethyl-4-isoxazolyl)ethyll-6a-methyl-perhydrocyclopenta[f][l]benzopyran-4a,7B-diol in 400 ml. of

acetone was cooled in an ice bath as a solution of 20 g.

(0.20 mole) of chromium trioxide in 100 ml. of 6N sulfuric acid was added dropwise over one-half hr. The mixture was stirred at for another one-half hr., and then at room temperature for l ,4 hr. It was then diluted with water and extracted with benzene. The benzene extracts were washed with water, .saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave racemic trans-4-[3-oxo-5 (3,5-dimethyl-4 -:isoxazolyl)pentyl]-la-methyl-perhydroindan-l ,5- dione as a pale yellow resin.

The crude trione trans-4-[3-oxo-5-(3,5 dimethyl-4- isoxazolyl) pentyl]-la-methyl-perhydroindan-1,5- dione was dissolved in 100 ml. of methanol, carefully degassed and placed under nitrogen. To the solution was added 1 g. of potassium hydroxide and the resulting black mixture was heated at reflux under nitrogen for l /4 hr. The cooled solution was diluted with water and extracted with benzene. The benzene extracts were washed with water and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave 8.33 g. of an orange solid which was filtered through 150 g. of Woelm neutral alumina, activity grade I. Elution with 3:1 benzenezether slowly brought off the desired isoxazole ene-dione (in later experiments, the use of activity grade Ill neutral alumina and elution with benzene was found to be superior). Crystallization from benzene-hexane gave the desired product as white prisms, m.p. l4l-l43.5. A sample from a similar preparation was crystallized again from benzene-hexane to give an analytically pure material, m.p. l4l.5-l 43.5.

Anal. Calcd. for C H NO C, 73.36; 'H, 7.70; N, 4.28; O, 14.66. Found: C, 73.39; H, 7.64; N, 4.38.

EXAMPLE Preparation of racemic l9-nor-Androst-4-en-3,l7- dione A mixture of 1.00 g. (3.06 mmoles) of the isoxazole enedione racemic trans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-l ,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e)indene-3,7(8l-l)-dione, prepared as described in Example 9, above, 60 mg. of 10 percent palladium on carbon, and 100 ml. of 3:] ethanol triethylamine was hydrogenated at atmospheric pressure and room temperature. Within 1 hour, one equivalent of hydrogen had been taken up and uptake had ceased. Normally, the product was not isolated. In one case however, the catalyst was removed by filtration and after solvent removal the crude product was crystallized from benzene-hexane to give pure racemic trans-anti-trans-anti-6-[ 3 ,5 -dim ethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-ll-l-benz[e]inden3,7(2H,6l-l)-dione as white prisms ofm.p. l37.5-l 395.

Anal. Calcd. for C H NO C, 72.92; H, 8.26; N, 4.25; O, 14.57. Found: C, 72.89; H, 7.93; N, 4.22, 4.34. To the hydrogenation mixture described above was added 10 ml. of a 1N potassium hydroxide in ethanol solution which had been carefully degassed and placed under nitrogen. After 1 9% hr., a second equivalent of win hydrogen had been taken up. The catalyst was removed by filtration and washed with fresh ethanol. Solvent removal-from the filtrates-gave thevinylogous amide as a pale'yellow resin which was immediately taken up in 25 ml. of butyl alcohol. This solution was carefully degassedand placed under nitrogen. To the flask was added ml. of a previously degassed 20 per cent aqueous potassium hydroxide solution. The resulting two phase mixture was heated atreflox under nitrogen for 20 hours. The cooled solution was diluted with water and extracted withether. The ether extracts were washed with water, 1N hydrochloric acid, water, and saturatedbrine and dried over anhydrous sodium sulfate. Solvent removal gave 690 mg. of yellow crystalline solid. This material was chro'matographed on 100 g. of Merck silica gel. Elution with 7:2 and 7:3 benzene: ether mixtures gave a light yellow solid which was homogenous by thin layer chromatography. Crystallization from acetone-isopropyl ether gave racemic l9- nor-androst 4-ene -3,l7-dione as a very pale yellow solid,m.p. l56.5 l5 8.5.

EXAMPLE 1 1 Preparation of trans-anti-trans-anti-6-[ 3 ,5-dimethyl- 4-isoxazolyl)methyl]-3,3,7,7,-bis(ethylenedioxy)-3amethyl-perhydrol l-l-benz e indene I A solutionof 654 mg. (2.0 mmoles) of the isoxazole ene dione racemic trans-antir6-(3,5-dimethyl-4-isox azolylmethyl)-3a-methyll ,2,-3a,4,5 9,9a,9b-octahydro-3H-benz(e)indene-3,7(8H)-dione prepared as described above, in 50 ml. of 3:1 ethanol: triethylamine containing 60 mg. of 10 percent palladium on carbon was hydrogenated at atmospheric pressure and room temperature. After 1.0 hr. uptake (1.0 equivalent) had ceased. The catalyst was removed by filtration and washed with fresh ethanol. Solvent removal from the filtrates gave the isoxazole dione, racemic trans-antitrans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3amethyl-3a,4,5,5a,8,9,9a,9b-octahydro-lH-benz[e]inden-3,7(2H,6l-l) dione as a colorless foam. This material was taken up in l5 ml. of ethylene glycol and 50 ml. of benzene, degassed, and placed under nitrogen. To the solution was added 400 mg. of 'p-toluenesulfonic acid monohydrate and the resulting mixture was heated at reflux under nitrogen, with azeotropic removal of water, for 21 hr. After 2 hr., Linde 3A molecular sieves were placed in the Dean-Stark trap. The pale pink solution was extracted with excess saturated aqueous sodium bicarbonate solution and brine-and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave the crude isoxazole diketal as a very pale yellow resin.

Pure isoxazole diketal, racemic trans-anti-trans-anti- 6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7- bis(ethylene-dioxy)-3a-methyl-perhydro-lll-benz [e]indene, was obtained from one such reaction by crystallization of the crude material from ether at -20 C. 9

Anal. Calcd. for C H NO C, 69.03; H, 8.45; N, 3.35; O,19.l6. Found: C, 69.34; H, 8.64; N, 3.35.

EXAMPLE l2 Preparation of racemic trans-anti-trans-anti-3,3,7,7- bis(ethylenedioxy)3a6-(3-oxobutyl)perhydrolI-l-benz[e]indene The crude noncrystalline isoxazole diketal racemic trans-antiransJantiJ6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)3a-methylperhydro-lH-benz[e]indene whose preparation is described in Example 11 above was dissolved in 40 ml. of ethanol containing 1.5 g. of potassium hydroxide and 80 mg. of percent palladium on carbon. The resulting solution was hydrogenated at atmospheric pressure and room temperature, under which conditions uptake of one equivalent of hydrogen took 4 hr. The catalyst was removed by filtration and washed with fresh ethanol. The solvent was removed from the filtrates until a residue of approximately 10 m1. remained. This solution of the vinylogous amide was degassed and placed under nitrogen. A previously degassed 20 per cent aqueous potassium hydroxide solution (50 ml.) was added and the resulting mixture was heated at reflux under nitrogen for 18 hr. The cooled solution was diluted with water and extracted with benzene. The

Anal. Calcd. for c,,-H,,o,; c, 69.81; H, 9.05; -o,

21.14. Found: C, 70.1 1; H, 8.99.

EXAMPLE 13 Preparation of racemic l9-nor-Androst-4-en-3, 1 7- dione The crude keto diketal, racemic trans-anti-transanti-3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)perhydro-lH-benz[e]indene whose preparation is described in Example 12 above, was suspended in 30 ml. of methanol, degassed, and placed under nitrogen. To the flask was added 3 ml. of 4N hydrochloric acid and the resulting solution was heated at reflux under nitrogen for 3 hr. The cooled mixture was diluted with water and extracted with benzene. The benzene solutions were washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Thin layer chromatography (1:1 benzene-ethyl acetate) of the solution showed only one very faint spot in addition to that corresponding to authentic l9-nor-androst-4-en-3,l7-dione. Solvent removal gave pale tan crystals which were chromatographed on 25 g. of Silica Gel. The material eluted with 9:1 and 8:2 benzene-ether mixtures was triturated with refluxing isopropyl ether and then cooled to -20 to give racemic l9-nor-androst-4-en-3,l7-dione as white prisms, m.p. 157-l 59.5.

EXAMPLE 14 Preparation of racemic trans-anti-6-[(3,5-dimethyl-4- isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3amethyl-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H- benz[e]indene A solution of 981 mg. (3.0 mmoles) of the isoxazole enedione, racemic trans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b, oc-

tahydro-3H-benz(e)indene-3,7(8H)-dione, 600 mg. of p-toluenesulfonic acid monohydrate and 15 ml. of ethylene glycol in 50 ml. of benzene was heated at reflux under nitrogen, with azeotropic removal of water, for 23 hr. After 2.0 hr., Linde 3A molecular sieves were placed in the Dean-Stark trap. The solution was cooled, washed with excess saturated aqueous 0 sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a colorless resin which was crystallized from ether-hexane to give the desired product, racemic trans-anti-6-[c93,5-dimethyl-4-isoxazolyl)methyl]- 3,3,7,7-bis (ethylenedioxy)-3a-methyl-2,3,3a, 4,6,7,8,9,9a,9b-decahydro-lH-benz[e]indene as a white crystalline solid, m.p. l20-l27. A sample from a similar preparation was crystallized again from etherhexane to give the analytically pure diketal as colorless microprisms of m.p. l27-l 29.

Anal. Calcd. for C H NO C, 69.37; H, 8.01; N, 3.37; O, 19.25. Found: C, 69.25; H, 8.25; N, 3.36.

EXAMPLE 15 Preparation of racemic trans-anti-3,3,7,7- bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-2,3,3a, 4,6,7,8,9,9a,9bd-decahydro-1H-benz[e]indene A solution of 830 mg. (2.0 mmoles) of the isoxazole ene diketal, racemic trans-anti-6-[(3,5-dimethyl-4- isoxazolyl)methyl]-3,3,7,7-bis(ethylenedioxy)-3amethyl-2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H- benz[e]indene prepared as described in Example 14 above, in 40 ml. of ethanol containing 2.0 g. of potassium hydroxide and mg. of 10 percent palladium on carbon was hydrogenated at atmospheric pressure and room temperature. Uptake (1.0 equivalent) of hydrogen ceased after 6 hr. The catalyst was removed by filtration and washed with fresh ethanol. The solvent was removed from the filtrate until a residue of 10 ml. remained. This solution of the vinylogous amide was degassed and placed under nitrogen. A previously degassed solution (50 ml.) of 20 percent aqueous potassium hydroxide was added and the resulting mixture was heated at reflux for 18 hr. The reaction mixture was then diluted with water and extracted with benzene. The benzene solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal gave a pale yellow resin which was homogenous to thin layer chromatography.

Crystallization of a sample from a similar preparation three times from isopropyl ether gave racemic transanti-3,3,7,7-bis (ethylenedioxy)-3a-methyl-6-(3-oxobutyl)-2,3,3a,4,6,7,8,9,9a,9b-decahydro-lH-benz[ e]indene as cream-white prisms, m.p. 80.0-83.5.

Anal. Calcd. for C H O C, 70.18; H, 8.57; O, 21.25. Found: C, 70.85, 70.69; H, 8.68, 8.51.

EXAMPLE 16 Preparation of racemic trans-anti-3a-methyl-6-(3-oxobutyl)-3a,4,5,9,9a,9b-hexahydro-Ill-benz[e]indene- 3,7-(2H,8H)-dione The crude keto ene diketal, racemic trans-anti- 3,3,7,7-bis-(ethylenedioxy)-3a-methyl-6-(3-ox0butyl)- 2,3,3a,4,6,7,8,9,9a,9b-decahydro-1H-benz[e]indene, whose preparation is described in Example 15 above, was dissolved in 30 ml. of 1:1 water-acetic acid,

degassed, placed under nitrogen, and heated at 90- 100 for 1% hr. The pale yellow solutionwas then cooled, diluted with water, and extracted with benzene. The benzene solutions were washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave 650 mg. of pale yellow resin. This material was crystallized three times from ether to give the pure trione, racemic trans-anti-3a-methyl-6-( 3-oxobutyl )-3a,4,5,9,9a,9b-hexahydrol H-be nz[e]inden-3,7(2H,8H)-dione as pale yellow prisms, m.p. l01.5-103.

Anal. Calcd. for C, H ,O C, 74.97; H, 8.39; O, 16.64. Found: C, 74.80, H, 8.54.

EXAMPLE l7 Preparation of 7-(3,5-dimethyl-4-isoxazolyl)-5- hydroxy-heptanoic acid lactone A solution of5.0 g. (22.4 mmoles) of racemic 7-(3,5- di-methyl-4-isoxazolyl)-5-hydroxyheptaonic acid lactone, 7.80 g. (50 mmoles) of menthol and 0.1 g. of p-toluenesulfonic acid in 100 ml. of benzene was heated at reflux under nitrogen for 16 hours. The solution was cooled and washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal at reduced pressure gave a mixture of diastereomeric esters as a pale yellow oil.-The desired R ester (the absolute configuration was determined by conversion of this material to l9-nor-androst-4-en-3,l7-dione) was obtained by preparative vapor phase chromatography. A solution of 2.10 g. of this ester in 50 ml. of 3N-aqueous potassium hydroxide was heated at reflux under nitrogen for 18 hours. The solution was cooled, extracted with ether, acidified with 3N-hydrochloric acid, saturated with sodium chloride and extracted 'with methylene chloride. The methylene chloride solutions were washed with brine and dried over anhydroussodium sulfate. Solvent removal gave a cloudy colorless resin. This crude product was heated to 200 C. at 0.2 mm., at which time the desired R-lacetone, 7-(3,5- dimethyl-4-isoxazoly1)-5-hydroxy-heptanoic acid lactone distilled as a colorless liquid.

EXAMPLE 18 2-(2-(-)-a-phenethylaminoethyl)-6-[2-(3,5- dimethyl-4-isoxazolyl)ethyl]-tetrahydropyran2-ol oxalate A solution of 22.3 g. (0.1 mole) of racemic 7-(3,5- dimethyl-4-isoxazolyl)-5-hydroxy heptanoic acid lactone, prepared as described in Example 7, in 330 ml. of dry tetrahydrofuran was cooled in a dry ice-acetone bath under nitrogen as 85 ml. of a 2 M solution of vinyl magnesium chloride in tetrahydrofuran was added at such a rate as to keep the temperature at -50 to 55f min.). Stirring was continued for 30 min. before the solution was hydrolyzed by the careful addition of 1 1 ml. of methanol. The solution was poured onto ice, 53 g. of ammonium chloride and 16 ml. of acetic acid and extracted with ether. The ether solutions were washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave 24.8 g. of crude 9-(3,5- dimethyl-4-isoxazolyl)-7-hydroxy-non-l-en-3-one as a yellow oil. This crude vinyl ketone was dissolved in 150 ml. of dry benzene. To this solution was added 8.56 g. of a-phenethylamine and the resulting mixture was stirred under nitrogen at 45 for 2.0 hr. The mixture was evaporated to dryness to give the crude Mannich base as 43.2 g. of yellow oil. This crude Mannich base was taken up in 150 ml. of ether and'mixed with a solution of 8.5 g. of oxalic acid in 100 ml. of ether. The oil which separated was removed and washed with ether. The oil was crystallized from acetone-benzene to give the desired oxalate as a white solid, mp. lll-l 14. Three further crystallizations from methanol-ether gave analytically pure 2-(2-(-)-aphenethylaminoethyl)-6-[2-('3,5 dimethyl-4-isoxazolyl)ethyl]tetrahydropyran-2-ol oxalateas a white 9 powder, m.p. l 18-l20.

Anal. Calcd. for C H N O C, 62.32;-H, 7.41; N, 6.06; O, 24.21. Found: C, 62.26; H, 7.38.

EXAMPLE l9 3-[ 2-( 3 ,5-Dimethyl-4-isoxazolyl )ethyl]-6a/3- methyl- 1 ,2,3 ,5,6,6a-hexahydrocyclopenta[f][ 1 benzopyran-7( 8H)-one A solution of 84.0 mg. of Z-methyl-cyclopentane- 1,3-dione in 5 ml. of toluene, 2 ml. of 95 percent acetic acid and 1 ml. of pyridine was carefully degassed, placed under nitrogen, and heated at reflux 1 min. To the solution was added 231 mg. of 2-(2-(-) aphenethylaminoethyl)-6-[2-(3,5-dimethyl-4-isoxazolyl)ethylI-tetrahydropyran-Z-ol oxalate, prepared as described in Example 18, and the resulting mixture was heated at reflux for 3 1% hr., the last one-half hr. with azeotropic removalof water. The cooled solution was diluted with benzene and washed with brine, saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave a brown oil which was chromatographed on 20 g. of activity III neutral alumina. Elution with hexane-benzene mixtures gave the desired dienol ether as pale yellow needles, mp. 88. Crystallization of this material from isopropyl ether gave analytically pure 3-[2-(3,5 -dimethyl-4-isoxazolyl)ethyl]-6a[3- methyl- 1 ,2,3,5,6, 6a-hexahydroc'yclopenta[f] l benzopyran-7(8H)-one as pale yellow needles, mp. -91.5.'

Anal. Calcd. for C H NO C, 73.36; H, 7.70; N, 4.28; O, 14.66. Found: C, 73.29; H, 7.74; N, 4.15.

EXAMPLE 20 mirifThe mixture was stirred at 0 for 15 min. and then without cooling for an additional 30 min. The reaction mixture was cautiously hydrolyzed at 0 with saturated aqueous sodium sulfate solution, dried over anhydrous sodium sulfate, and filtered. Solvent removal from the filtrates gave crude 3-[2-(3,5-dimethyl-4-isoxazolyl )ethyl]-6aB-methyl- 1 ,2,3,5 ,6,6a,7,8-octahydrocyclopenta[f][1]benzopyran-7B-ol as a pale orange glass.

The crude alcohol was taken up in 20 ml. of tetrahydrofuran. To this solution was added 100 mg. of a 5 percent palladium on carbon catalyst and the mixture was hydrogenated at atmospheric pressure and room temperature. The uptake of one equivalent of hydrogen took hr. Removal of the catalyst by filtration, followed by solvent removal at reduced pressure gave trans-3-[2-(3,5-dimethy1-4-isoxazoly1)ethy1]-6amethy1-1,2,3,5 ,6,6a,7,8,9 ,9a-decahydrocyclopenta[f] [l]benzopyran-7B-ol as a pale orange resin. This crude enol ether was taken up in ml. of acetone, degassed, and placed under nitrogen. To this solution was added 10 ml. of 1N sulfuric acid and the resulting mixture was stirred atroom temperaturefor 1 1% hr., poured into saturated aqueous sodium bicarbonate solution and extracted with chloroform. The chloroform solutions were washed with saturated aqueous sodium bicarbonate solution and saturated brine and dried over anhydrous sodium sulfate. Solvent removal gave the crude hemiketal, trans-3-[2-(3,5-dimethyl-4-isoxazolyl )ethyl -6a-methyl-perhydrocyc1openta [f] 1 ]benzopyran-4a,7b-diol as an orangish-colored foam.

The crude hemiketal was dissolved in 20 ml. of acetone and cooled in an ice bath as a solution of 1.5 g. of chromium trioxide in 7.5 ml. of 6N sulfuric acid was added over 20 min. The resulting suspension was stirred at 0 for 40 min. and then for an additional 1 /& -hr. without cooling. It was then poured into water and extracted with benzene. It was then poured into water and extracted with benzene. The benzene solutions were washed with water, saturated aqueous sodium bicarbonate solution, and brine and dried over anhydrous sodium sulfate. Solvent removal gave crude trans-4-[3-oxo-5(3,5-dimethyl-4-isoxazoly1)pentyl]- la-methyl-perhydroindan-1,5-dione as a pale orange resin. This material was taken up in 20 ml. of methanol, degassed and placed under nitrogen. To the flask was added 200 mg. of sodium hydroxide and the resulting dark solution was heated at reflux 2.0 hr., cooled, diluted with water, and extracted with benzene. The benzene solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal gave the crude isoxazole ene dione which was chromatographed on neutral alumina, activity 111. The material eluted with a 95:5 benzene-ether mixture was crystallized from isopropyl ether to give pure trans-anti-6- [(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl- 1 ,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e ]indene-3,7( 8 1-1)-dione as colorless needles, m.p. 8587.5.

EXAMPLE 21 Preparation of trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3B-tertiary butoxyl,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene- 7-one In a dry flask, 520 mg. of 55 percent sodium hydride dispersion was washed with pentane to remove the mineral oil. The sodium hydride was suspended in 100 ml. of freshly distilled 1,2-dimethoxyethane and 2.76 g. of trans-anti-3a-methyl-3B-tertiary butoxyl,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene- 7-one was added to the suspension. The mixture was heated at reflux under nitrogen for 1.0 hr. A solution of 1.75 g. of 4-ch1oromethyl-3,S-dimethylisoxazole in 20 m1. of 1,2-dimethoxyethane was then added at reflux over a periodof 4 hr. The suspension was heated at reflux an additional 1 56 hr., cooled, diluted with water, and extracted with benzene. The benzene solutions were washed with brine and dried over anhydrous sodium sulfate. The orange resin obtained upon solvent removal was chromatographed on 200 g. of silica gel. The material obtainedby elution with :5 and 90:10 benzene-ether mixtures was crystallized from etherhexane to give analytically pure trans-anti-6-[(3,5- dimethyl-4-isoxazo1yl)methyll-3a-methyl-3fi-tertiary butoxy- 1 ,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e ]indene-7-one, m.p. 125.5-126.5.

Anal. Calcd. for C I-1 N 0 C, 74.76; H, 9.15; N, 3.63; O, 12.45. Found: C, 74.88; H, 9.38; N, 4.67.

EXAMPLE 22 Preparation of trans-anti-6-[(3,5-dimethyl-4-isox azoly1)methy1]-3a-methyl-3,8-hydroxyl,2,3,3a,4,5,8,9,9a,9b-decahydro-7H-benz[e]indene 7-one A solution of 1.1519 g. of trans-anti-6-[(3,5- dimethyl-4-isoxazolyl)methyl]-3a-methyl-3B-tertiary butoxy- 1 ,2,3 ,3a,4,5 ,8,9,9a,9b-decahydro-7H-benz[e ]indene-7-one, prepared as described in Example 21, and 1.1 g. of p-toluenesulfonic acid monohydrate in ml. of benzene was degassed, placed under nitrogen and heated at reflux for 1.0 hr. The cooled solution was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave a yellowish resin which was crystallized from isopropyl ether to give the desired alcohol as fine white needles, m.p. 127-l27.5.

Anal. Calcd. C H N O C, 72.92; H, 8.26; N, 4.25; O, 14.57. Found: C, 73.25; H, 8.49; N, 4.16.

EXAMPLE 23 Preparation of trans-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl1-3a-methyl-1,2,3a,4,5 ,9,9a,9b-octahydro-3H-benz[e]indene-3,7(8H) dione A solution of 415 mg. of trans-anti-6-[(3,5- dimethyl-4-isoxazo1y1)rnethyl]-3a-methyl-3B-hydroxy- 1,2,3,3a4,5,8,9,9a,9b-decahydro-7l-1-benz[e]indene-7- one, prepared as described in Example 22, in 25 ml. of acetone was cooled in an ice bath as 1.0 ml. of Jones chromium trioxide reagent was added over 5 min. The solution was stirred 10 min., poured into aqueous sodium bisulfit'e, and extracted with benzene. The benzene solutions were washed with water, saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave a colorless foam which, on crystallization from isopropyl ether, gave analytically pure trans-anti-6-[(3,5- dimethy1-4-isoxazolyl)methyl]-3a-methyll,2,3a,4,5 ,9,9a,9b-octahydro-3H-benz[e]indene-3,7(8 l-1)-dione as white needles, m.p. 85.587.5.

Anal. Calcd. for C I-1 N 0 C, 73.36; 11,770; N, 4.28;O, 14.66. Found: C, 73.67;?1, 7.95; N, 4.15.

EXAMPLE 24 Preparation of l9-nor-androst-4-en-3,l 7-dione.

A solution of 1.308 g. of trans-anti-6-[(3,5- dimethyl-4-isoxazolyl)methyl]-3a-methyl-l ,2,3a,4,5, 9,9a,9b-octahydro-3l-l -benz[e]inden-3,7(8l-l)-dione, prepared as described above in Example 20, in 100 ml. of 3:1 ethanol-triethylamine containing 80 mg. of percent palladium on carbon, was hydrogenated at atmospheric pressure and room temperature. After l /2 hr., the uptake of hydrogen ceased. Filtration, followed by solvent removal, gave trans-anti-trans-6-[(3,5- dimethyl-4-isoxazolyl)-methyl]-3a-methyl-3a,4,5,5a, 8,9,9a,9b-octahydro-lH+benz[e]inden-3,7(2H,6H)- dione as a colorless foam. This crude product was taken up in 10 ml. of ethylene glycol and 75 ml. of benzene and heated with 750 mg. of p-toluenesulfonic acid at reflux under nitrogen, with azeotropic removal of water, for hr. The cooled solution was washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave trans-anti-trans-6-[(3,5- dimethyl-4-isoxazolyl)methyl]-3,3,7,7- bis(ethylenedioxy )-3a-methyl-perhydrol l-l-benz[e]indene as a pale yellow resin. A solution of the crude isoxazole diketal in 100 ml. of ethanol containing 2.5 g. of potassium hydroxide and 100 mg. of 10 percent palladium on carbon was hydrogenated at atmospheric pressure and room temperature. The uptake of one equivalent of hydrogen took 5.0 hr. The catalyst was removed by filtration and the solvent was removed from the filtrates until a residue of approximately 5 ml. remained. To this solution of the vinylogous amide was added 150 ml. of 20 percent aqueous potassium hydroxide. The mixture was degassed, placed under nitrogen, heated at reflux under nitrogen for 16 hr., cooled, and extracted with benzene. The benzene solutions were washed with brine and dried over anhydrous sodium sulfate. Solvent removal gave trans-anti-trans- 3,3,7,7-bis-(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)- perhydro-lH-benz[e]indene as a colorless resin. This material was taken up in 50 ml. of methanol, degassed and placed under nitrogen. To the solution was added 5 ml. of 4N-hydrochloric acid and the resulting solution was heated at reflux for 3.0 hr. The cooled solution was diluted with water and extracted with benzene. The benzene solutions were washed with water, saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave crude l9-nor-androstene dione as a pale tan crystalline solid. Filtration of this material through silica gel with 9:1 benzenezether followed by.crystallization from acetone-hexane gave l9-nor-androst-4- en-3,l 7-dione as shiny platelets, m.p. l73-l 74.

EXAMPLE Preparation of trans-anti-3a-methyl-6-(3-oxobutyl)-3a,4,5 ,9 ,9a,9b-hexahydrol H-benz[e]inden-3 ,7(2 H,8H)-dione.

A solution of 981 mg. of trans-anti-6-[(3,5- dimethyl-4-isoxazolyl)methyl]-3a-methyll,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e ]inden-3,7-( 8 H)-dione, prepared as described in Example 20, and 600 mg. of p-toluenesulfonic acid in 15 ml. of ethylene glycol and 50 ml. of benzene was degassed, placed under nitrogen and heated at reflux with azeotropic removal of water, for 23 hr. The cooled solution was washed with excess saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave trans-anti-6-[( 3,5 -dimethyl-4-isoxazolyl)methyl] 3,3,7,7-bis- (ethylenedioxy)-3a-methyl-2,3,3a,4,6,7,8,9,9a,9bdecahydro-lH-benz[e]indene as a colorless resin. This material was taken up in 60 ml. of ethanol containing 3.0 g. of potassium hydroxide and 100 mg. of 10 per cent palladium on carbon and hydrogenated at atmospheric pressure and room temperature. Uptake of one equivalent of hydrogen took 6.0 hr. The catalyst was removed by filtration and the solvent was removed from the filtrates until approximately 10 ml. remained. To this solution of vinylogous amide was added ml. of 20 per cent aqueous potassium hydroxide and the resulting mixture was heated at reflux under nitrogen for 18 hours. The cooled mixture was diluted with water and extracted with benzene. The benzene solutions were washed with brine and dried over anhydrous 'sodium sulfate. Solvent removal gave trans-anti- 3,3,7,7-bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)- 2,3,3a,4,6,7,8,9,9a,9b-decahydro-lH-benz[e]indene as a very pale yellow resin. This material was taken up in 50 ml. of I11 water-acetic acid, degassed, placed under nitrogen, and heated at 90l00 for 1 5% hr. The solution was cooled, diluted with water and extracted with benzene. The benzene solutions were washed with saturated aqueous sodium bicarbonate solution and brine and dried over anhydrous sodium sulfate. Solvent removal gave crude trione as a pale yellow resin. Crystallization of this material from isopropylether gave trans-anti3a-methyl-6-(3-oxobutyl)- 3a,4,5,9,9a,9b-hexahydro-lH-benz[e]inden-3,7-(2 H,8l-l)-dione, m.p. 8 1 .5.

EXAMPLE 26 Preparation of racemic l9-nor-9B,l0a-androst-4-en- 3,l7-dione A mixture containing 655 mg. (2.0 mM) of racemic trans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3amethyl-l ,2,3a,4,5,9,9a,9b-octahydro-3H-benz(e)indene-3,7(8H)-dione, 250 mg. of 7 percent Pd/BaSO 0.5 ml. of 48 percent HBr and 20 ml. of ethanol was hydrogenated at atmospheric pressure and room temperature for a period of 8 hours. The catalyst was removed by filtration and washed with fresh ethanol. The filtrates were diluted with benzene and washed twice with brine and once each with sodium bicarbonate and brine. The organic layer was then dried over sodium sulfate and the solvent removed to give 650 mg. of a bone-white solid. This material was dissolved in approximately 3 ml. of hot benzene to which was added approximately 15ml. ofether and the solution was cooled to 0 C. After filtration there was obtained 430 mg. (65 percent yield) of fine white needles of trans-anti-cis-anti-6- 3 ,5 -dimethyl4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-lH-benz[e]inden- 3,7(2H,6H)-dione. An analytical sample was prepared by dissolving a small amount of the aforesaid material in methylene chloride, filtering and removing solvent. The residue was crystallized from benzene/ether to give very tiny white needles, mp. l96l98.5. Anal. Calcd. for C OH NO C, 72.92; H, 8.26; N, 4.25. Found: C, 72.57; H, 8.26; N, 4.13.

um: m

A solution containing 658 mg. (2.0 mM) of the above retrodione, 200 mg. of p-toluenesulfonic acid hydrate, 15 ml. of ethylene glycol and 60 ml. of benzene was degassed, placed under a nitrogen atmosphere and heated at reflux with removal of water for 22 hours. The solution was cooled, diluted with benzene and extracted with saturated aqueous sodium bicarbonate solution (2X), water (2X) and brine. The organic phase was dried over sodium sulfate and the solvent removed to give a cream-white solid representing crude, racemic trans-anti-trans-cis-anti-6[(3,5- dimethyl-4isoxazolyl)methyl]-3,3,7,7- bis( ethylenedioxy )-3a-methyl-perhydrol H-benz[e]indene.

The above isoxazolyl diketal was suspended in 40 ml. of ethanol containing 1.5 g. of KOl-l. There was then added 150 mg. of a 5 percent Pd/C catalyst and the resulting mixture was hydrogenated at atmospheric pressure and room temperature for approximately 1.5 hours. The catalyst was then removed by filtration and washed with fresh ethanol. The combined filtrates were evaporated to yield a residue of about ml. A total of 50 ml. of percent aqueous KOH was then added to the residue and the resulting solution was degassed, placed under nitrogen and reheated at reflux for 20 hours. The mixture was cooled, poured into water and extracted with benzene. The benzene extracts were washed with brine and dried over sodium sulfate. Solvent removal gave a cloudy light yellow resin comprising crude, racemic trans-anticis-anti-3,3,7,7- bis(ethylenedioxy)-3a-methyl-6-(3-oxobutyl)perhydro-1H-benz[e]indene.

Crude ketone material was taken up in 20 ml. of dioxane, degassed, placed under a nitrogen atmosphere and cooled in an ice bath. A total of 1.0 ml. of percent HCl was then added dropwise over two minutes. The mixture was cooled another 5 minutes and was then allowed to stir at room temperature for 22 hours. The light yellow solution was poured into excess saturated aqueous sodium bicarbonate solution and extracted with benzene. The combined benzene solutions were washed with sodium bicarbonate, brine and then dried over sodium sulfate. Solvent removal gave 603 mg. of light orange resin which crystallized slowly. This material was chromatographed on silica gel and crystallized from approximately 10 ml. of methylenechloride/ether and cooling to 20 to give 272 mg. (50 percent yield) of small white prisms which exhibited slight melting at l4l-142; m.p. l48l52. Recrystallization from approximately 5 ml. of methylene chloride/ether with cooling at 20 gave 239 mg. of small white prisms, m.p. l48.5l52 (softening at 142) representing pure l9-nor-9B,l0a-androst-4-en-3 l 7-dione.

Anal. Calcd:C 1-l ,O C, 79.37; H, 8.88.

Found: C, 79.07; H, 8.88.

EXAMPLE 27 Preparation of trans-anti-cis-anti-6-[(3,5-dimethyl-4- isoxazolyl)-methyl]-3,3,7,7-bis(ethylenedioxy)-3amethyl-perhydro-l H-benz[ e]indene A mixture containing 2.4 g. (7.3 mM) of racemic trans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-lH-benz[e]inden-3,7(2H,6H)dione, 600 mg.

of p-toluenesulfonic acid hydrate, 25 ml. of ethylene glycol and 150 ml. of benzene was degassed. placed under nitrogen and heated at reflux with azeotropic removal of water for 22 hours. The resulting solution was cooled, washed with saturated aqueous sodium bicarbonate, water (2X) and brine. The organic phase was dried over sodium sulfate and the solvent removed to give 3.1 g. of a white solid. This material was dissolved in approximately 4 ml. of methylene chloride/l percent triethylamine. To this solution was added 50 ml. of ether. After cooling to 20 there was obtained 2.805 g. of shiny pale yellow prisms, m.p. 186-9 (fast heating). Recrystallization from 6 ml. of methylene chloride/ 1 percent triethylamine plus 50 ml. of ether with cooling to 0 gave 1.85 of colorless prisms, m.p. l88.5-191 representing pure, racemic trans-anti-cisanti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]3,3,7,7 bis( ethylenedioxy)-3a-methyl-perhydrol H-benz[ e] indene. Anal. Calcd. for C ,H O N: C, 69.03; H, 8.45; N, 3.35. Found: C, 69.14; H, 8.32; N, 3.27.

EXAMPLE 28 Preparation of ()-l 9-nor-9/3,10a-androst-4-en-3, l 7- dione A mixture containing 655 mg. (2.0 mM) of trans-anti-6-( 3 ,5dimethyl-4-isoxazolylmethyl)-3amethyl- 1 ,2,3a,4,5,9,9a,9b-octahydro-3H-benz[e] inden-3,7(8l-l)-dione, 10 percent Pd/BaSO 1.0 ml. of 47 percent HBr and 40 ml. of ethanol was hydrogenated at atmospheric pressure and room temperature for about 5 /2 hours. The catalyst was removed by filtration and washed with fresh ethanol. The combined filtrate was eluted with benzene, washed with water, brine, saturated aqueous sodium bicarbonate solution and then with brine. The organic layers were dried over sodium sulfate and the solvent removed to yield a pale yellow resin which crystallized upon standing. After chromatography on silica gel the product was dissolved in 2 ml. of methylene-chloride and 20 m1. of ether was added. After seeding and cool ing to 20 there was obtained 295 mg. (45 percent yield) of fine white needles, m.p. 169 l72.5 with some previous slight softening. An analytical sample of pure (+)trans-anti-cis-anti-6-[(3,5-dimethyl-4-isoxazolyl)methyl]-3a-methyl-3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz[3]inden-3,7(2H,6H)-dione was obtained by recrystallization from methylene chloride/ether with cooling to 0, m.p. l70.5l 74.

Anal. Calcd. for C H O N: C, 72.92; H, 8.26; N, 4.25.

Found: C, 72.80; H, 8.40; N, 4.14.

[01],, +l22.9 (c 0.895, CHCl U.V. A 222 mu( e=4,750).

A solution containing 1.730 g. (5.25 mM) of the above dione and 400 mg. of p-toluenesulfonic acid hydrate in 25 ml. of ethylene glycol and ml. of benzene was degassed, placed under nitrogen and heated at reflux with azeotropic removal of water for 22 hours. The cooled solution was washed with satu-' rated aqueous sodium bicarbonate (2X), water (2X) and brine. The organic phase was dried over sodium sulfate and the solvent removed after filtration to give a pale yellow resin as a residue. The resin comprising ()-trans-anti-cis-anti 6- 3 ,5 dimethyl-4-isoxazolyl methyl]-3,3,7,7-bis(ethylenedioxy)-3a-methyl-perhydro-1l-l-benz[e]-indene was dissolved in 80 ml. of ethanol containing 3.5 g. of K011 and there was then added to this solution a total of 400 mg. of percent Pd/C catalyst. The resulting mixture was hydrogenated at atmospheric pressure and room temperature. Uptake of hydrogen ceased after about 1 /2 hours. The catalyst was removed by filtration and washed with fresh ethanol. The combined ethanol filtrates were stripped of solvent until a residue of approximately 25 ml. remained.

To this solution of vinylogous amide was added-80 ml. of 20 percent aqueous 'KOl-l and the resulting mixture was degassed placed under nitrogen and heated at reflux for 12 hours. The cooled solution was poured into water and extracted with benzene. The combined benzene extracts were washed with water and brine. The organic phase was dried over sodium sulfate and the solvent removed to give crude keto diketal as a yellow resin. The material was taken up in 50 ml. of dioxane, degassed and placed under nitrogen. The solution was cooled in an ice bath and when the solvent began to solidify a total of 3.0 ml. of 25 percent HCl was added dropwise over 3 minutes. The mixture was stirred at 0 for an additional minutes and then at room temperature for 22 hours. The mixture was then diluted with benzene and then washed with water, brine, saturated aqueous sodium bicarbonate and then brine again. The organic phase was dried over sodium sulfate and the solvent removed to yield a yellow resin. The crude steroid was purified by chromatography over silica gel followed by crystallization from acetone/isopopyl ether 1:10 with cooling to 20 to yield ()-l9-nor-9B,10a-androst-4-en-3,l7-dione as white needles, mp. 131135.5. Recrystallization from acetone/isopropyl ether as above gave white needles of pure product, m.p. 132135.5.

Anal. Calcd. for C H O C, 79.37; H, 8.88

Found: C, 79.24; H, 8.87.

[a],, =23.9 (c= 1.055, CHCl U.V. A 239-240 mpt e 17,300).

EXAMPLE 29 Preparation of ()-trans-anti-cis-anti-6-[(3,5- dimethyl-4-isoxazolyl)methyl]-3,3,7,7-bis(ethylene dioxy)-3a-methyl-perhydro- 1 l-l-benz[e]indene A mixture containing 1.76 g. (5.33 mM) of trans-anti-cis-anti-6-[ 3 ,5-dimethyl-4-isoxazolyl)methyl)-3a-methyl-3a,4,5,5a,8,9,9a,9b-0ctahydro-1l-l-benz[e]inden-3,7(2l-l,6l-l)-dione, 400 mg. of p-tolu'enesulfonic acid hydrate, ml. of ethylene glycol and 100 ml. of benzene was degassed, placed under nitrogen and heated at reflux with azeotropic removal of water for 22 hours. The cooled solution was washed with saturated aqueous sodium bicarbonate (2X), water (2X) and brine. The organic phase was dried over sodium sulfate and then the solvents removed to give 2.34 g. of a colorless glass which soon crystallized. Crystallization from acetone/isopropyl ether after cooling to gave 2.03 g. of white needles, m.p. 155-l58. Recrystallization from methylene chloride/isopropyl ether with cooling to 20 gave 1.775 g. of fine white needles, mp. 156l58.5 of the above-captioned product.

Anal. Calcd. for C H NO C, 69.03; H, 8.45; N,3.35.

Found: C, 68.93; H, 8.47; N, 3.36.

[011 31.6 (c 0.87 CHCl U.V. A 223-224 m J.( e=4,900).

EXAMPLE'30 Preparation of racemic 19-nor-9B,l0a-androst-4-en- 3,17-dione via tricyclic triketone A suspension containing 725 mg. (1.92 mM) of trans-anti-cis-anti-3,3,7,7-bis(ethylenedioxy)-3amethyl-6-(3-oxobutyl)-perhydro-1 I-l-benz[e]indene in 30 m1. of 1:1 acetic acid/waterwas degassed, placed under nitrogen and heated at for 1 1% hour. the cooled mixture was poured into water and the resulting mixture was extracted with benzene. The combined benzene extracts were washed with brine, saturated sodium bicarbonate solution and brine again. The organic phase was dried over sodium sulfate and after removal of the solvent there was obtained a pale yellow resin comprising crude racemic, trans-anti-cis-anti-3amethy1-6-( 3-oxobutyl )-per-hydro- 1 H-benz[ e inden- 3,7-dione. This material was taken up in 25 m1. of 2- methoxyethanol and 1.0 ml. of pyrrolidine was added. The mixture was degassed, placed under nitrogen and heated at 95-100 for 16 hours. A total of 10 ml. of acetate buffer was added and heating was continued for an additional 2 hours. The mixture was poured into water and extracted with benzene. The benzene solutions were washed with brine, saturated aqueous bicarbonate and brine and dried over sodium sulfate. Removal of the solvents gave a light brown resin which crystallized on standing. This resin was chromatographed on silica gel using benzene/ether 8:2 as eluent yielded the above-captioned product as light orange crystals. Recrystallization from methylene chloride/ether with cooling to 20 yielded light yellow prisms, m.p. 147-151 (softening at 138).

EXAMPLE 31 Preparation of racemic 13-ethyl-9B,l0a-gon-4-en-3,17 dione A mixture containing 1.032 g. (3.0 mM) of racemic trans-anti-3a-ethyl- 1 ,2,3a,4,5 ,9,9a,9b-octahydro-3l-lbenz[e]inden-3,7(8H)-dione (prepared in analogous fashion to that described in Examples 8 and 9 with the exception that 2-ethylcyclopentane-1,3-dione was employed instead of the corresponding methyl compound), 300 mg. of 10 percent Pd/BaSO, and 60 of ethanol was stirred at room temperature for 50 minutes. A total of 1.5 m1. of 45 percent HBr was then added and the resulting mixture was hydrogenated at atmospheric pressure and room temperature for a period of about 6 /2 hours at which time uptake of hydrogen ceased. The catalyst was removed by filtration and washed with fresh ethanol. The combined ethanol filtrates were diluted with benzene, washed with water and brine, saturated aqueous sodium bicarbonate solution and then with brine again. The organic phase was dried over sodium sulfate and the solvent removed to give 1.043 g. of a white solid. This material was chromatographed on silica gel first using benzene/ether at 8:2 and finally at 7:3. The latter eluates were combined and evaporated to give 956 mg. of a white solid which on crystallization from methylene chloride/ether 1:10 and cooling to --20 gave 781 mg. of fine white needles, mp. 174-176.5 (sint. l60-162 Recrystallization with the same procedure gave 752 mg. (72 percent yield) of pure, racemic trans-anti-cis- 

2. The compounds as in claim 1 wherein m is 1; R1 is ethyl or methyl; R15 and R16 are each independently lower alkyl; Z is carbonyl or R8 is hydrogen; R7 is lower alkyl, hydrogen, lower alkanoyl or monocyclic aryl; the compound of Formula I has a trans-anti configuration; and the compound of Formula II has a trans-anti-trans configuration.
 3. The compounds as in claim 1 wherein m is 1; R1 is methyl or ethyl; R15 and R16 are each independently lower alkyl; Z is carbonyl or R8 is hydrogen, R7 is lower alkyl, hydrogen, lower alkanoyl or monocyclic aroyl; the compound of formula I has a trans-anti configuration; and the compound of formula II has a trans-anti-cis configuration.
 4. A compound as in claim 2 which is trans-anti-6-(3,5-dimethyl-4-isoxazolylmethyl)-3a-methyl-1,2,3a,4,5,9,9a,9b -octahydro-3H-benz(e)indene-3,7(8H)-dione.
 5. A compound as in claim 2 which is trans-anti-trans-6-((3,5-dimethyl-4-isoxazolyl)methyl)-3a-methyl-3a, 4,5,5a,8,9,9a,9b-octahydro-1H-benz(e)indene-3,7(2H,6H)-dione
 6. A compound as in claim 3 which is trans-anti-cis-6-((3,5-dimethyl-4-isoxazolyl)methyl)-3a-methyl -3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz(e)indene-3,7(2H,6H)-dione.
 7. A compound as in claim 3 which is trans-anti-cis-6-((3,5-dimethyl-4-isoxazolyl)-methyl)-3a-ethyl -3a,4,5,5a,8,9,9a,9b-octahydro-1H-benz(e)indene-3,7(2H,6H)-dione. 